Warfarin, 3-((alpha)-acetonylbenzyl)-4-hydroxycoumarin, is an anticoagulant having demonstrated utility as a blood thinning and/or antithrombotic agent to prevent blood from clotting. Warfarin has been granted regulatory approval for the prophylaxis and/or treatment of venous thromboembolisms (VE) including deep vein thrombosis (DVT) and pulmonary embolism; prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement atrial fibrillation, to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction. (See e.g., Physicians Desk Reference, 56th Edition, 2002, pages 1243-1248).
Warfarin is a potent anticoagulant having a relatively narrow therapeutic index (International Normalized Ratio (INR) of 2-4). Being potent means that relatively low concentrations of the drug in the blood are sufficient to produce the desired effect. Having a narrow therapeutic index means that the therapeutic effect is obtained only over a narrow range of concentrations; and in case of warfarin, concentrations below or above the range are associated with serious, and potential lethal side effects. The most serious risks associated with anticoagulant therapy with warfarin are hemorrhage in any tissue or organ and, necrosis and/or gangrene of skin and other tissues, possibly resulting in death or permanent disability.
Use of warfarin is further complicated by delay of a few days before the onset of the desired anticoagulant effect. Warfarin has a complex dose response relationship that makes safe and effective use a challenge. Treatment of each patient is a highly individualized matter. Once therapy is commenced, careful monitoring is necessary to strike a balance between underdosing and overdosing. For most indications, dosage is controlled by periodic determinations of prothrombin time (PT), International Normalized Ratio (INR) or other suitable coagulation tests. This combination of characteristics, coupled with the patient-to-patient variations in response to warfarin, dictates extreme caution in the administration of warfarin.
Until recently no therapeutic agent has been effective in long-term management of prophylaxis or treatment of recurrent venous thromboembolism due to high risk associated with anticoagulant therapy. A recent study (PREVENT) effectively demonstrated the use of low dose oral warfarin therapy for the long-term prevention of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism, without significant adverse effects to the patients, such as major hemorrhage or other potential side effects of warfarin (See Ridker et al., The New England Journal of Medicine (NEJM), 348(15), pages 1425-1434).
Existing therapies consisting of oral administration of warfarin have several disadvantages. For example, frequent periodic doses result in peaks and valleys in blood concentration (Cpeak˜4 hr), and standard error are conventionally associated with those blood concentration swings. Further, lack of individual compliance and improper adherence to treatment schedule would result in warfarin concentrations below or above the prescribed dose causing serious, and potential lethal side effects. Thus there is a need for improved and effective prophylaxis and treatment of thromboembolic disorders.
The transdermal administration of warfarin offers several advantages. The peaks and valleys in blood concentration resulting from frequent periodic doses of warfarin would be eliminated and replaced by substantially constant plasma concentration. This would not only improve individual compliance but also would eliminate the alternating periods of high side-effects and ineffective blood concentrations associated with period dosing. Administering the agent through the skin directly into the blood stream would also eliminate first-pass metabolism of orally administered warfarin. However, transdermal administration of high doses of warfarin would result in unacceptable skin irritation and sensitization.
Previously described transdermal systems have been developed to administer warfarin in response to the aforementioned challenges. For example, U.S. Pat. No. 6,365,178 discloses transdermal systems containing hydrophilic salts of hydrophobic drugs dissolved in aqueous dispersion of hydrophobic pressure sensitive adhesives. Notwithstanding some success, previously described systems have not been entirely satisfactory for transdermal Transdermal administration of low-dose warfarin provides an effective regimen for long-term management of prophylaxis or treatment of recurrent venous thromboembolism due to high risk associated with anticoagulant therapy. A transdermal device capable of administering low-doses of warfarin would result in improved therapy by maintaining steady-state warfarin concentrations in the blood for periods of up to 7 days, preferably about 3 days to about 7 days.